Flexible Circuit Electrode Array Embedded in a Cured Body

ABSTRACT

Polymer materials are useful as electrode array bodies for neural stimulation. They are particularly useful for retinal stimulation to create artificial vision, cochlear stimulation to create artificial hearing, and cortical stimulation, and many related purposes. The pressure applied against the retina, or other neural tissue, by an electrode array is critical. Too little pressure causes increased electrical resistance, along with electric field dispersion. Too much pressure may block blood flow. Common flexible circuit fabrication techniques generally require that a flexible circuit electrode array be made flat. Since neural tissue is almost never flat, a flat array will necessarily apply uneven pressure. Further, the edges of a flexible circuit polymer array may be sharp and cut the delicate neural tissue. It is advantageous that the array edges not contact tissue.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of application Ser. No. 11/924,696,entitled “Retinal Prosthesis with a New Configuration”, which is adivisional application of application Ser. No. 11/523,965, entitled“Retinal Prosthesis with a New Configuration”, filed Sep. 19, 2006,which application claims the benefit of U.S. Provisional Application No.60/718,660, entitled “System Architecture and Stimulation Methods for aRetinal Prosthesis”, filed Sep. 19, 2005, the disclosures of which isincorporated herein by reference.

This application claims the benefit of U.S. Provisional Application No.60/718,769, entitled “System for Testing and Configuring a RetinalProsthesis”, filed Sep. 19, 2005, the disclosures of which isincorporated herein by reference.

This application claims the benefit of U.S. Provisional Application No.60/718,779, “Transretinal Flexible Circuit Electrode Array”, filed Sep.19, 2005, the disclosures of all which is incorporated herein byreference.

This application claims the benefit of U.S. patent application Ser. No.11/521,281, “Transretinal Flexible Circuit Electrode Array”, filed Sep.13, 2006, the disclosures of which is incorporated herein by reference.

This application claims the benefit of U.S. patent application Ser. No.11/413,689, “Flexible circuit electrode array”, filed Apr. 28, 2006,which is a Continuation-In-Part of U.S. application Ser. No. 11/207,644,“Flexible circuit electrode array”, filed Aug. 19, 2005 which claims thebenefit of U.S. Provisional Application No. 60/676,008 “Thin FilmElectrode Array”, filed Apr. 28, 2005, the disclosures of all areincorporated herein by reference.

This application is a Continuation-in-Part of the U.S. patentapplication Ser. No. 10/918,112 “Retinal prosthesis”, filed Aug. 13,2004, which claims the benefit of U.S. Provisional Application No.60/574,130 “Retinal Prosthesis”, filed May 25, 2004, the disclosures ofall are incorporated herein by reference.

GOVERNMENT RIGHTS NOTICE

This invention was made with government support under grant No.R24EY12893-01, awarded by the National Institutes of Health. Thegovernment has certain rights in the invention.

FIELD OF THE INVENTION

The present invention is generally directed to neural stimulation andmore specifically to an improved electrode array for neural stimulation.

BACKGROUND OF THE INVENTION

In 1755 LeRoy passed the discharge of a Leyden jar through the orbit ofa man who was blind from cataract and the patient saw “flames passingrapidly downwards.” Ever since, there has been a fascination withelectrically elicited visual perception. The general concept ofelectrical stimulation of retinal cells to produce these flashes oflight or phosphenes has been known for quite some time. Based on thesegeneral principles, some early attempts at devising prostheses foraiding the visually impaired have included attaching electrodes to thehead or eyelids of patients. While some of these early attempts met withsome limited success, these early prosthetic devices were large, bulkyand could not produce adequate simulated vision to truly aid thevisually impaired.

In the early 1930's, Foerster investigated the effect of electricallystimulating the exposed occipital pole of one cerebral hemisphere. Hefound that, when a point at the extreme occipital pole was stimulated,the patient perceived a small spot of light directly in front andmotionless (a phosphene). Subsequently, Brindley and Lewin (1968)thoroughly studied electrical stimulation of the human occipital(visual) cortex. By varying the stimulation parameters, theseinvestigators described in detail the location of the phosphenesproduced relative to the specific region of the occipital cortexstimulated. These experiments demonstrated: (1) the consistent shape andposition of phosphenes; (2) that increased stimulation pulse durationmade phosphenes brighter; and (3) that there was no detectableinteraction between neighboring electrodes which were as close as 2.4 mmapart.

As intraocular surgical techniques have advanced, it has become possibleto apply stimulation on small groups and even on individual retinalcells to generate focused phosphenes through devices implanted withinthe eye itself.

This has sparked renewed interest in developing methods and apparatus toaid the visually impaired. Specifically, great effort has been expendedin the area of intraocular retinal prosthetic devices in an effort torestore vision in cases where blindness is caused by photoreceptordegenerative retinal diseases; such as retinitis pigmentosa and agerelated macular degeneration which affect millions of people worldwide.

Neural tissue can be artificially stimulated and activated by prostheticdevices that pass pulses of electrical current through electrodes onsuch a device. The passage of current causes changes in electricalpotentials across visual neuronal membranes, which can initiate visualneuron action potentials, which are the means of information transfer inthe nervous system.

Based on this mechanism, it is possible to input information into thenervous system by coding the sensory information as a sequence ofelectrical pulses which are relayed to the nervous system via theprosthetic device. In this way, it is possible to provide artificialsensations including vision.

One typical application of neural tissue stimulation is in therehabilitation of the blind. Some forms of blindness involve selectiveloss of the light sensitive transducers of the retina. Other retinalneurons remain viable, however, and may be activated in the mannerdescribed above by placement of a prosthetic electrode device on theinner (toward the vitreous) retinal surface (epiretinal).

This placement must be mechanically stable, minimize the distancebetween the device electrodes and the visual neurons, control theelectronic field distribution and avoid undue compression of the visualneurons.

In 1986, Bullara (U.S. Pat. No. 4,573,481) patented an electrodeassembly for surgical implantation on a nerve. The matrix was siliconewith embedded iridium electrodes. The assembly fit around a nerve tostimulate it.

Dawson and Radtke stimulated cat's retina by direct electricalstimulation of the retinal ganglion cell layer. These experimentersplaced nine and then fourteen electrodes upon the inner retinal layer(i.e., primarily the ganglion cell layer) of two cats. Their experimentssuggested that electrical stimulation of the retina with 30 to 100 μAcurrent resulted in visual cortical responses. These experiments werecarried out with needle-shaped electrodes that penetrated the surface ofthe retina (see also U.S. Pat. No. 4,628,933 to Michelson).

The Michelson '933 apparatus includes an array of photosensitive deviceson its surface that are connected to a plurality of electrodespositioned on the opposite surface of the device to stimulate theretina. These electrodes are disposed to form an array similar to a “bedof nails” having conductors which impinge directly on the retina tostimulate the retinal cells. U.S. Pat. No. 4,837,049 to Byers describesspike electrodes for neural stimulation. Each spike electrode piercesneural tissue for better electrical contact. U.S. Pat. No. 5,215,088 toNorman describes an array of spike electrodes for cortical stimulation.Each spike pierces cortical tissue for better electrical contact.

The art of implanting an intraocular prosthetic device to electricallystimulate the retina was advanced with the introduction of retinal tacksin retinal surgery. De Juan, et al. at Duke University Eye Centerinserted retinal tacks into retinas in an effort to reattach retinasthat had detached from the underlying choroid, which is the source ofblood supply for the outer retina and thus the photoreceptors. See,e.g., E. de Juan, et al., 99 Am. J. Ophthalmol. 272 (1985). Theseretinal tacks have proved to be biocompatible and remain embedded in theretina, and choroid/sclera, effectively pinning the retina against thechoroid and the posterior aspects of the globe. Retinal tacks are oneway to attach a retinal electrode array to the retina. U.S. Pat. No.5,109,844 to de Juan describes a flat electrode array placed against theretina for visual stimulation. U.S. Pat. No. 5,935,155 to Humayundescribes a retinal prosthesis for use with the flat retinal arraydescribed in de Juan.

SUMMARY OF THE INVENTION

Polymer materials are useful as electrode array bodies for neuralstimulation. They are particularly useful for retinal stimulation tocreate artificial vision, cochlear stimulation to create artificialhearing, or cortical stimulation for many purposes. Regardless of whichpolymer is used, the basic construction method is the same. A layer ofpolymer is laid down, commonly by some form of chemical vapordeposition, spinning, meniscus coating or casting. A layer of metal,preferably platinum, is applied to the polymer and patterned to createelectrodes and leads for those electrodes. Patterning is commonly doneby photolithographic methods. A second layer of polymer is applied overthe metal layer and patterned to leave openings for the electrodes, oropenings are created later by means such as laser ablation. Hence thearray and its supply cable are formed of a single body. Alternatively,multiple alternating layers of metal and polymer may be applied toobtain more metal traces within a given width.

The pressure applied against the retina, or other neural tissue, by anelectrode array is critical. Too little pressure causes increasedelectrical resistance between the array and retina, along with electricfield dispersion. Too much pressure may block blood flow causing retinalischemia and hemorrhage. Pressure on the neural retina may also blockaxonal flow or cause neuronal atrophy leading to optic atrophy. Commonflexible circuit fabrication techniques such as photolithographygenerally require that a flexible circuit electrode array be made flat.Since the retina is spherical, a flat array will necessarily apply morepressure near its edges, than at its center. Further, the edges of aflexible circuit polymer array may be quite sharp and cut the delicateretinal tissue. It is advantageous to embed the flexible circuitelectrode array in a curved body to impart a curvature to the array.Further, it is advantageous to add material along the edges of aflexible circuit array. Particularly, it is advantageous to add materialthat is more compliant than the polymer used for the flexible circuitarray.

The novel features of the invention are set forth with particularity inthe appended claims. The invention will be best understood from thefollowing description when read in conjunction with the accompanyingdrawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of the implanted portion of the preferredretinal prosthesis.

FIG. 2 is a side view of the implanted portion of the preferred retinalprosthesis showing the fan tail in more detail.

FIG. 3A-3E depict molds for forming the flexible circuit array in acurve.

FIG. 4 depicts an alternate view of the invention with ribs to helpmaintain curvature and prevent retinal damage.

FIG. 5 depicts an alternate view of the invention with ribs to helpmaintain curvature and prevent retinal damage fold of the flexiblecircuit cable and a fold A between the circuit electrode array and theflexible circuit cable.

FIG. 6 depicts a cross-sectional view of the prosthesis shown inside ofthe eye with an angle in the fold of the flexible circuit cable and afold between the circuit electrode array and the flexible circuit cable.

FIG. 7 depicts the implanted portion including a twist in the flexiblecircuit cable to reduce the width of a sclerotomy and a sleeve topromote sealing of the sclerotomy.

FIG. 8 depicts the flexible circuit array before it is folded andattached to the implanted portion.

FIG. 9 depicts the flexible circuit array folded.

FIG. 10 depicts a flexible circuit array with a protective skirt.

FIG. 11 depicts a flexible circuit array with a protective skirt bondedto the back side of the flexible circuit array.

FIG. 12 depicts a flexible circuit array with a protective skirt bondedto the front side of the flexible circuit array.

FIG. 13 depicts a flexible circuit array with a protective skirt bondedto the back side of the flexible circuit array and molded around theedges of the flexible circuit array.

FIG. 14 depicts a flexible circuit array with a protective skirt bondedto the back side of the flexible circuit array and molded around theedges of the flexible circuit array and flush with the front side of thearray.

FIG. 15 is an enlarged view of a single electrode within the flexiblecircuit electrode array.

FIG. 16 depicts the flexible circuit array before it is folded andattached to the implanted portion containing an additional fold betweenthe flexible electrode array and the flexible cable.

FIG. 17 depicts the flexible circuit array of FIG. 16 folded containingan additional fold between the flexible electrode array and the flexiblecable.

FIG. 18 depicts a flexible circuit array of FIG. 17 with a protectiveskirt and containing an additional fold between the flexible electrodearray and the flexible cable.

FIG. 19 depicts a top view of a flexible circuit array and flexiblecircuit cable showing an additional horizontal angel between theflexible electrode array and the flexible cable.

FIG. 20 depicts another variation without the horizontal angel betweenthe flexible electrode array and the flexible cable but with anorientation of the electrodes in the flexible electrode array as shownfor the variation in FIG. 19.

FIG. 21 depicts a top view of a flexible circuit array and flexiblecircuit cable wherein the array contains a slit along the length axis.

FIG. 22 depicts a top view of a flexible circuit array and flexiblecircuit cable wherein the array contains a slit along the length axiswith two attachment points.

FIG. 23 depicts a flexible circuit array with a protective skirt bondedto the back side of the flexible circuit array with a progressivelydecreasing radius.

FIG. 24 depicts a flexible circuit array with a protective skirt bondedto the front side of the flexible circuit array with a progressivelydecreasing radius.

FIG. 25 depicts a flexible circuit array with a protective skirt bondedto the back side of the flexible circuit array and molded around theedges of the flexible circuit array with a progressively decreasingradius.

FIG. 26 depicts a flexible circuit array with a protective skirt bondedto the back side of the flexible circuit array and molded around theedges of the flexible circuit array and flush with the front side of thearray with a progressively decreasing radius.

FIG. 27 depicts a plan view of the flexible circuit array with a skirtcontaining a grooved and rippled pad instead of a suture tab.

FIG. 28 depicts an enlarged plan view of a portion of the skirt shown inFIG. 27 containing a grooved and rippled pad and a mattress suture.

FIG. 29 depicts a flexible circuit array with a protective skirt bondedto the front side of the flexible circuit array with individualelectrode windows.

FIG. 30 depicts a flexible circuit array with a protective skirt bondedto the back side of the flexible circuit array and molded around theedges of the flexible circuit array with individual electrode windows.

FIGS. 31-36 show several surfaces to be applied on top of the cable.

FIG. 37 depicts the top view of the flexible circuit array beingenveloped within an insulating material.

FIG. 38 depicts a cross-sectional view of the flexible circuit arraybeing enveloped within an insulating material.

FIG. 39 depicts a cross-sectional view of the flexible circuit arraybeing enveloped within an insulating material with open electrodes andinsulating material between the electrodes.

FIG. 40 depicts a cross-sectional view of the flexible circuit arraybeing enveloped within an insulating material with open electrodes.

FIG. 41 depicts a cross-sectional view of the flexible circuit arraybeing enveloped within an insulating material with electrodes on thesurface of the material.

FIG. 42 depicts a cross-sectional view of the flexible circuit arraybeing enveloped within an insulating material with electrodes on thesurface of the material inside the eye with an angle in the fold of theflexible circuit cable and a fold between the circuit electrode arrayand the flexible circuit cable.

FIG. 43 depicts an enlarged cross-sectional portion side view of theflexible circuit array being enveloped within an insulating materialwith electrodes on the surface of the material inside the eye.

FIG. 44 shows the flexible circuit array before it is folded andattached to the implanted portion.

FIG. 45 shows the flexible circuit array folded.

FIG. 46 shows a cross-sectional view of an eye showing the placement ofthe retinal implant and associated electronics.

FIG. 47 shows a cross-sectional view of a retina showing the tissuelayers and placement of the retinal implant in the retina for electricalstimulation of the retina.

FIG. 48 shows a cross-sectional view of an eye showing placement of theretinal implant for drug delivery.

FIG. 49 shows a cross-sectional view of an eye showing the placement ofthe subretinal implant.

FIG. 50 shows a cross-sectional view of an eye showing the placement ofthe subretinal implant.

FIG. 51 shows a cross-sectional view of a retina showing the tissuelayers and placement of the retinal implant in the retina for drugdelivery.

FIG. 52 shows a cross-sectional view of the eye with the preferredretinal prosthesis.

FIG. 53 shows a cross-sectional view of the eye with the preferredretinal prosthesis.

FIG. 54 shows stimulus pulses elicit 2 phases of neuronal spikes.

FIG. 55 shows a measurement of spontaneous spikes.

FIG. 56 shows a review of epiretinal stimulation thresholds.

FIG. 57 shows an electrode diameter.

FIG. 58 shows a respond to 10 stimulus pulses.

FIG. 59 shows a shows the correlation between height and electricalstimulation threshold in these 4 subjects.

FIG. 60 shows a two point discrimination performance.

FIG. 61 shows a relative position performance.

FIG. 62 shows a spatial location of phosphenes associated withindividual electrodes.

FIG. 63 shows spike thresholds for two stimulation configurations.

FIG. 64 shows multiple site stimulation.

FIG. 65 shows a fundus photo and flourescein angiogram after 3 month ofthe preferred trans-retinal implant in a rabbit.

FIG. 66 shows measurements of produced by a stimulating electrode.

FIG. 67 shows short pulses only produce early phase spiking.

FIG. 68 shows brightness rating as a function of stimulation current fortwo observers.

FIG. 69 shows short electrical pulses.

FIG. 70 shows the effect of burst frequency.

FIG. 71 shows the current required to reach threshold for a 200 msinterval of pulses.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following description is of the best mode presently contemplated forpracticing the invention. This description is not to be taken in alimiting sense, but is made merely for the purpose of describing thegeneral principles of the invention. The scope of the invention shouldbe determined with reference to the claims.

FIG. 1 shows a perspective view of the implanted portion of thepreferred retinal prosthesis. A flexible circuit 1 includes a flexiblecircuit electrode array 10 which is mounted by a retinal tack (notshown) or similar means to the epiretinal surface. The flexible circuitelectrode array 10 is electrically coupled by a flexible circuit cable12, which pierces the sclera and is electrically coupled to anelectronics package 14, external to the sclera.

The electronics package 14 is electrically coupled to a secondaryinductive coil 16. Preferably the secondary inductive coil 16 is madefrom wound wire. Alternatively, the secondary inductive coil 16 may bemade from a flexible circuit polymer sandwich with wire traces depositedbetween layers of flexible circuit polymer. The electronics package 14and secondary inductive coil 16 are held together by a molded body 18.The molded body 18 may also include suture tabs 20. The molded body 18narrows to form a strap 22 which surrounds the sclera and holds themolded body 18, secondary inductive coil 16, and electronics package 14in place. The molded body 18, suture tabs 20 and strap 22 are preferablyan integrated unit made of silicone elastomer. Silicone elastomer can beformed in a pre-curved shape to match the curvature of a typical sclera.However, silicone remains flexible enough to accommodate implantationand to adapt to variations in the curvature of an individual sclera. Thesecondary inductive coil 16 and molded body 18 are preferably ovalshaped. A strap 22 can better support an oval shaped coil.

It should be noted that the entire implant is attached to and supportedby the sclera. An eye moves constantly. The eye moves to scan a sceneand also has a jitter motion to improve acuity. Even though such motionis useless in the blind, it often continues long after a person has losttheir sight. By placing the device under the rectus muscles with theelectronics package in an area of fatty tissue between the rectusmuscles, eye motion does not cause any flexing which might fatigue, andeventually damage, the device.

FIG. 2 shows a side view of the implanted portion of the retinalprosthesis, in particular, emphasizing the fan tail 24. When implantingthe retinal prosthesis, it is necessary to pass the strap 22 under theeye muscles to surround the sclera. The secondary inductive coil 16 andmolded body 18 must also follow the strap 22 under the lateral rectusmuscle on the side of the sclera. The implanted portion of the retinalprosthesis is very delicate. It is easy to tear the molded body 18 orbreak wires in the secondary inductive coil 16. In order to allow themolded body 18 to slide smoothly under the lateral rectus muscle, themolded body 18 is shaped in the form of a fan tail 24 on the endopposite the electronics package 14.

The flexible circuit 1 is a made by the following process. First, alayer of polymer (such as polyimide, fluoro-polymers, silicone or otherpolymers) is applied to a support substrate (not part of the array) suchas glass. Layers may be applied by spinning, meniscus coating, casting,sputtering or other physical or chemical vapor deposition, or similarprocess. Subsequently, a metal layer is applied to the polymer. Themetal is patterned by photolithographic process. Preferably, aphoto-resist is applied and patterned by photolithography followed by awet etch of the unprotected metal. Alternatively, the metal can bepatterned by lift-off technique, laser ablation or direct writetechniques.

It is advantageous to make this metal thicker at the electrode and bondpad to improve electrical continuity. This can be accomplished throughany of the above methods or electroplating. Then, the top layer ofpolymer is applied over the metal. Openings in the top layer forelectrical contact to the electronics package 14 and the electrodes maybe accomplished by laser ablation or reactive ion etching (RIE) orphotolithograph and wet etch. Making the electrode openings in the toplayer smaller than the electrodes promotes adhesion by avoidingdelaminating around the electrode edges.

The pressure applied against the retina by the flexible circuitelectrode array is critical. Too little pressure causes increasedelectrical resistance between the array and retina. It should be notedthat while the present invention is described in terms of application tothe retina, the techniques described are equally applicable to manyforms of neural stimulation. Application to the retina requires a convexspherical curve. Application to the cochlea requires a constant curve inone dimension and a spiral curve in the other. Application to thecerebral cortex requires a concave spherical curve. Cortical stimulationis useful for artificial vision or hearing, touch and motor control forlimb prostheses, deep brain stimulation for Parkinson's disease andmultiple sclerosis, and many other applications.

Common flexible circuit fabrication techniques such as photolithographygenerally require that a flexible circuit electrode array be made flat.Since the retina is spherical, a flat array will necessarily apply morepressure near its edges, than at its center. With most polymers, it ispossible to curve them when heated in a mold. By applying the rightamount of heat to a completed array, a curve can be induced that matchesthe curve of the retina. To minimize warping, it is often advantageousto repeatedly heat the flexible circuit in multiple molds, each with adecreasing radius. FIG. 3 illustrates a series of molds according to thepreferred embodiment. Since the flexible circuit will maintain aconstant length, the curvature must be slowly increased along thatlength. As the curvature 30 decreases in successive molds (FIGS. 3A-3E)the straight line length between ends 32 and 34, must decrease to keepthe length along the curvature 30 constant, where mold 3E approximatesthe curvature of the retina or other desired neural tissue. The moldsprovide a further opening 36 for the flexible circuit cable 12 of thearray to exit the mold without excessive curvature.

It should be noted that suitable polymers include thermoplasticmaterials and thermoset materials. While a thermoplastic material willprovide some stretch when heated a thermoset material will not. Thesuccessive molds are, therefore, advantageous only with a thermoplasticmaterial. A thermoset material works as well in a single mold as it willwith successive smaller molds. It should be noted that, particularlywith a thermoset material, excessive curvature in three dimensions willcause the polymer material to wrinkle at the edges. This can causedamage to both the array and the retina. Hence, the amount of curvatureis a compromise between the desired curvature, array surface area, andthe properties of the material.

Referring to FIG. 4, the edges of the polymer layers are often sharp.There is a risk that the sharp edges of a flexible circuit will cut intodelicate retinal tissue. It is advantageous to add a soft material, suchas silicone, to the edges of a flexible circuit electrode array to roundthe edges and protect the retina. Silicone around the entire edge maymake the flexible circuit less flexible. So, it is advantageous toprovide silicone bumpers or ribs to hold the edge of the flexiblecircuit electrode array away from the retinal tissue. Curvature 40 fitsagainst the retina. The leading edge 44 is most likely to cause damageand is therefore fit with molded silicone bumper. Also, edge 46, wherethe array lifts off the retina can cause damage and should be fit with abumper. Any space along the side edges of curvature 40 may cause damageand may be fit with bumpers as well. It is also possible for theflexible circuit cable 12 of the electrode array to contact the retina.It is, therefore, advantageous to add periodic bumpers along theflexible circuit cable 1′2.

It is also advantageous to create a reverse curve or service loop in theflexible circuit cable 12 of the flexible circuit electrode array togently lift the flexible circuit cable 12 off the retina and curve itaway from the retina, before it pierces the sclera at a sclerotomy. Itis not necessary to heat curve the service loop as described above, theflexible circuit electrode array can simply be bent or creased uponimplantation. This service loop reduces the likelihood of any stressexerted extraocularly from being transmitted to the electrode region andretina. It also provides for accommodation of a range of eye sizes.

With existing technology, it is necessary to place the implanted controlelectronics outside of the sclera, while a retinal flexible circuitelectrode array must be inside the sclera in order to contact theretina. The sclera is cut through at the pars plana, forming asclerotomy, and the flexible circuit passed through the sclerotomy. Aflexible circuit is thin but wide. The more electrode wires, the widerthe flexible circuit must be. It may be difficult to seal a sclerotomyover a flexible circuit wide enough to support enough wires for a highresolution array. A narrow sclerotomy is preferable.

FIG. 5 depicts a further embodiment of the part of the prosthesis shownin FIG. 4 with a fold A between the circuit electrode array 10 and theflexible circuit cable 12. The angle in the fold A also called ankle hasan angle of 1°-180°, preferably 80°-120°. The fold A is advantageoussince it reduces tension and enables an effective attachment of theflexible electrode circuit array 10 to the retina.

FIG. 6 depicts a side view of the prosthesis insight of the eye with anangle K of the flexible circuit cable 12 and a fold A between thecircuit electrode array 10 and the flexible circuit cable 12. The angleK is about 45°-180° and preferably 80°-100°. The fold K also called kneeis advantageous because it decreases pressure which would be applied bythe flexible circuit cable 10.

FIG. 7 shows the implanted portion of the retinal prosthesis includingthe additional feature of a gentle twist or fold 48 in the flexiblecircuit cable 12, where the flexible circuit cable 12 passers throughthe sclera (scierotomy). The twist may be a simple sharp twist, or fold48; or it may be a longer twist, forming a tube. While the tube isrounder, it reduces the flexibility of the flexible circuit. A simplefold 48 reduces the width of the flexible circuit with only minimalimpact on flexibility.

Further, silicone or other pliable substance may be used to fill thecenter of the tube or fold 48 formed by the twisted flexible circuitcable 12. Further it is advantageous to provide a sleeve or coating 50that promotes healing of the sclerotomy. Polymers such as polyimide,which may be used to form the flexible circuit cable 12 and flexiblecircuit electrode array 10, are generally very smooth and do not promotea good bond between the flexible circuit cable 12 and scleral tissue. Asleeve or coating of polyester, collagen, silicone, Gore-tex or similarmaterial would bond with scleral tissue and promote healing. Inparticular, a porous material will allow scleral tissue to grow into thepores promoting a good bond.

Alternatively, the flexible circuit electrode array 10 may be insertedthrough the sclera, behind the retina and placed between the retina andchoroid to stimulate the retina subretinally. In this case, it isadvantageous to provide a widened portion, or stop, of the flexiblecircuit cable 12 to limit how far the flexible circuit electrode arrayis inserted and to limit the transmission of stress through the sclera.The stop may be widening of the flexible circuit 1 or it may be addedmaterial such as a bumper or sleeve.

Human vision provides a field of view that is wider than it is high.This is partially due to fact of having two eyes, but even a single eyeprovides a field of view that is approximately 90° high and 140° to 160°degrees wide. It is therefore, advantageous to provide a flexiblecircuit electrode array 10 that is wider than it is tall. This isequally applicable to a cortical visual array. In which case, the widerdimension is not horizontal on the visual cortex, but corresponds tohorizontal in the visual scene.

FIG. 8 shows the flexible circuit electrode array prior to folding andattaching the array to the electronics package 14. At one end of theflexible circuit cable 12 is an interconnection pad 52 for connection tothe electronics package 14. At the other end of the flexible circuitcable 12 is the flexible circuit electrode array 10. Further, anattachment point 54 is provided near the flexible circuit electrodearray 10. A retina tack (not shown) is placed through the attachmentpoint 54 to hold the flexible circuit electrode array 10 to the retina.A stress relief 55 is provided surrounding the attachment point 54. Thestress relief 55 may be made of a softer polymer than the flexiblecircuit, or it may include cutouts or thinning of the polymer to reducethe stress transmitted from the retina tack to the flexible circuitelectrode array 10. The flexible circuit cable 12 is formed in a dog legpattern so than when it is folded at fold 48 it effectively forms astraight flexible circuit cable 12 with a narrower portion at the fold48 for passing through the sclerotomy.

FIG. 9 shows the flexible circuit electrode array after the flexiblecircuit cable 12 is folded at the fold 48 to form a narrowed section.The flexible circuit cable 12 may include a twist or tube shape as well.With a retinal prosthesis as shown in FIG. 1, the bond pad 52 forconnection to the electronics package 14 and the flexible circuitelectrode array 10 are on opposite side of the flexible circuit. Thisrequires patterning, in some manner, both the base polymer layer and thetop polymer layer. By folding the flexible circuit cable 12 of theflexible circuit electrode array 10, the openings for the bond pad 52and the electrodes are on the top polymer layer and only the top polymerlayer needs to be patterned.

Also, since the narrowed portion of the flexible circuit cable 12pierces the sclera, shoulders formed by opposite ends of the narrowedportion help prevent the flexible circuit cable 12 from moving throughthe sclera. It may be further advantageous to add ribs or bumps ofsilicone or similar material to the shoulders to further prevent theflexible circuit cable 12 from moving through the sclera.

Further it is advantageous to provide a suture tab 56 in the flexiblecircuit body near the electronics package to prevent any movement in theelectronics package from being transmitted to the flexible circuitelectrode array 10. Alternatively, a segment of the flexible circuitcable 12 can be reinforced to permit it to be secured directly with asuture.

An alternative to the bumpers described in FIG. 4, is a skirt ofsilicone or other pliable material as shown in FIGS. 10, 11, 12, and 13.A skirt 60 covers the flexible circuit electrode array 10, and extendsbeyond its edges. It is further advantageous to include wings 62adjacent to the attachment point to spread any stress of attachment overa larger area of the retina. There are several ways of forming andbonding the skirt 60. The skirt 60 may be directly bonded throughsurface activation or indirectly bonded using an adhesive.

Alternatively, a flexible circuit electrode array 10 may be layeredusing different polymers for each layer. Using too soft of a polymer mayallow too much stretch and break the metal traces. Too hard of a polymermay cause damage to delicate neural tissue. Hence a relatively hardpolymer, such a polyimide may be used for the bottom layer and arelatively softer polymer such a silicone may be used for the top layerincluding an integral skirt to protect delicate neural tissue.

The simplest solution is to bond the skirt 60 to the back side (awayfrom the retina) of the flexible circuit electrode array 10 as shown inFIG. 11. While this is the simplest mechanical solution, sharp edges ofthe flexible circuit electrode array 10 may contact the delicate retinatissue. Bonding the skirt to the front side (toward the retina) of theflexible circuit electrode array 10, as shown in FIG. 12, will protectthe retina from sharp edges of the flexible circuit electrode array 10.However, a window 62 must be cut in the skirt 60 around the electrodes.Further, it is more difficult to reliably bond the skirt 60 to theflexible circuit electrode array 10 with such a small contact area. Thismethod also creates a space between the electrodes and the retina whichwill reduce efficiency and broaden the electrical field distribution ofeach electrode. Broadening the electric field distribution will limitthe possible resolution of the flexible circuit electrode array 10.

FIG. 13 shows another structure where the skirt 60 is bonded to the backside of the flexible circuit electrode array 10, but curves around anysharp edges of the flexible circuit electrode array 10 to protect theretina. This gives a strong bond and protects the flexible circuitelectrode array 10 edges. Because it is bonded to the back side andmolded around the edges, rather than bonded to the front side, of theflexible circuit electrode array 10, the portion extending beyond thefront side of the flexible circuit electrode array 10 can be muchsmaller. This limits any additional spacing between the electrodes andthe retinal tissue.

FIG. 14 shows a flexible circuit electrode array 10 similar to FIG. 13,with the skirt 60, flush with the front side of the flexible circuitelectrode array 10 rather than extending beyond the front side. Whilethis is more difficult to manufacture, it does not lift the electrodesoff the retinal surface as with the array in FIG. 10. It should be notedthat FIGS. 11, 13, and 14 show skirt 60 material along the back of theflexible circuit electrode array 10 that is not necessary other than forbonding purposes. If there is sufficient bond with the flexible circuitelectrode array 10, it may advantageous to thin or remove portions ofthe skirt 60 material for weight reduction.

Referring to FIG. 15, the flexible circuit electrode array ismanufactured in layers. A base layer of polymer 70 is laid down,commonly by some form of chemical vapor deposition, spinning, meniscuscoating or casting. A layer of metal 72 (preferably platinum) is appliedto the polymer base layer 70 and patterned to create electrodes 74 andtraces for those electrodes. Patterning is commonly done byphotolithographic methods. The electrodes 74 may be built up byelectroplating or similar method to increase the surface area of theelectrode 74 and to allow for some reduction in the electrodes 74 overtime. Similar plating may also be applied to the bond pads 52 (FIGS.8-10). A top polymer layer 76 is applied over the metal layer 72 andpatterned to leave openings for the electrodes 74, or openings arecreated later by means such as laser ablation. It is advantageous toallow an overlap of the top polymer layer 76 over the electrodes 74 topromote better adhesion between the layers, and to avoid increasedelectrode reduction along their edges. The overlapping top layerpromotes adhesion by forming a clamp to hold the metal electrode betweenthe two polymer layers. Alternatively, multiple alternating layers ofmetal and polymer may be applied to obtain more metal traces within agiven width.

FIG. 16 depicts the flexible circuit array 1 before it is folded andattached to the implanted portion containing an additional fold Abetween the flexible electrode array 10 and the flexible cable 12. Theangle in the fold A, also called ankle, has an angle of 1°-180°,preferably 80°-120°. The ankle is advantageous in the process ofinserting the prostheses in the eye and attaching it to the retina.

FIG. 17 depicts the flexible circuit array 1 of FIG. 16 foldedcontaining an additional fold A between the flexible electrode array 10and the flexible cable 12. The flexible circuit array as shown in FIGS.8 and 16 differ by the fold A from each other.

FIG. 18 depicts a flexible circuit array of FIG. 17 with a protectiveskirt 60 and containing an additional fold A between the flexibleelectrode 10 array and the flexible cable 12. The flexible circuit arrayas shown in FIGS. 10 and 18 differ by the fold A from each other.

FIG. 19 depicts a top view of a flexible circuit array and flexiblecircuit cable showing the additional horizontal angle H between theflexible electrode array 10 and the flexible cable 12. The angle H isfrom about 1° to about 90° and preferably from about 30° to about 60°.

FIG. 20 depicts another variation without the horizontal angle H betweenthe flexible electrode array 10 and the flexible cable 12 but with anorientation of the electrodes in the flexible electrode array 12 asshown in FIG. 19 for a flexible electrode array 10. The grid ofelectrodes 13 has the angle H with the flexible cable which can be thesame as the angle H in the flexible electrode array 10 of FIG. 19.

Both variation shown in FIGS. 19 and 20 have the advantage that theelectrodes are oriented horizontally if they are inserted into the eye.Further, both variations as shown in FIGS. 19 and 20 can alsoadditionally contain a fold K (FIG. 6).

FIG. 21 depicts a top view of a flexible circuit array and flexiblecircuit cable as shown in FIGS. 10 and 18 wherein the array contains aslit along the length axis.

FIG. 22 depicts a skirt of silicone or other pliable material as shownin FIGS. 10 to 14. A skirt 60 covers the flexible circuit electrodearray 10, and extends beyond its edges. In this embodiment of thepresent invention the flexible circuit electrode array contains a slit80 along the lengths axis. Further, according to this embodiment, theskirt of silicone or other pliable material contains preferably at leasttwo attachment points 81 and stress reliefs 82 are provided surroundingthe attachment points 81. The attachment points 81 are locatedpreferably on the skirt 60 outside the flexible circuit electrode 10 andare positioned apart as far as possible from each other. The two tacks81 are far enough apart not to cause tenting, therefore fibrosis betweenthe two tacks which cause a traction detachment of the retina.Furthermore, the polyimide is completely between the two tacks, whichalso reduce the possibility of tenting. Also, this orientation of tackskeeps the tacks away from the axons, which arise from the ganglion cellswhich are intended to be activated. The wings 62 serve as external tabsor strain reliefs. The multiple tacks prevent rotation of the array.

The stress relief 82 may be made of a softer polymer than the flexiblecircuit, or it may include cutouts or thinning of the polymer to reducethe stress transmitted from the retina tack to the flexible circuitelectrode array 10.

FIG. 23 depicts a flexible circuit array 10 with a protective skirt 60bonded to the back side of the flexible circuit array 10 with aprogressively decreasing radius.

FIG. 24 depicts a flexible circuit array 10 with a protective skirt 60bonded to the front side of the flexible circuit array 10 with aprogressively decreasing radius.

FIG. 25 depicts a flexible circuit array 10 with a protective skirt 60bonded to the back side of the flexible circuit array 10 and moldedaround the edges of the flexible circuit array with a progressivelydecreasing radius.

FIG. 26 depicts a flexible circuit array 10 with a protective skirt 60bonded to the back side of the flexible circuit array 10 and moldedaround the edges of the flexible circuit array and flush with the frontside of the array with a progressively decreasing radius.

FIG. 27 depicts a plan view of the array with a skirt 60 containing agrooved and rippled pad 56 a instead of a suture tab 56. This pad 56 ahas the advantage of capturing a mattress suture 57. A mattress suture57 has the advantage of holding the grooved or rippled pad 56 a in twoplaces as shown in FIG. 28. Each suture 57 is fixed on the tissue onfour places 59. A mattress suture 57 on a grooved or rippled mattress 56a therefore enhances stability.

FIG. 29 depicts in cross-section a flexible circuit array 10 with aprotective skirt 60 bonded to the front side of the flexible circuitarray 10 with individual electrode windows 62 and with material,preferably silicone, between the electrodes 11.

FIG. 30 depicts in cross-section a flexible circuit array with aprotective skirt bonded to the back side of the flexible circuit arrayand molded around the edges of the flexible circuit array withindividual electrode windows and with material, preferably siliconebetween the electrodes 11.

FIGS. 31-36 show several surfaces to be applied on top of the cable. Thesurfaces are thin films containing a soft polymer, preferably silicone.FIG. 31 shows a flange 15: A flange 15 can be a solid film of materialcontaining silicone added to the surface of the polymer containingpolyimide. FIGS. 32-34 show a ladder 15 a: A ladder 15 a is a flangewith material removed from central portions in some shape 19. FIG. 35shows a skeleton structure 15 b. A skeleton 15 b is a flange withmaterial removed from perimeter portions in some shape 21. FIG. 36 showsa structure 15 c with beads 23 and bumpers 25. A bead 23 is materialadded to perimeter portions of the polymer cable in some shape withoutmaterial being added on the central area. A bumper 25 can be an extendedor continuous version of the beaded approach. Both embodiments arehelpful in preventing any possible injury of the tissue by the polymer.

FIG. 37 depicts the top view of the flexible electrode array 10 beingenveloped within an insulating material 11. The electrode array 10comprises oval-shaped electrode array body 10, a plurality of electrodes13 made of a conductive material, such as platinum or one of its alloys,but that can be made of any conductive biocompatible material such asiridium, iridium oxide or titanium nitride. The electrode array 10 isenveloped within an insulating material 11 that is preferably silicone.“Oval-shaped” electrode array body means that the body may approximateeither a square or a rectangle shape, but where the corners are rounded.This shape of an electrode array is described in the U.S. PatentApplication No. 20020111658, entitled “Implantable retinal electrodearray configuration for minimal retinal damage and method of reducingretinal stress” and No. 20020188282, entitled “Implantable drug deliverydevice” to Rober J. Greenberg et al., the disclosures of both beingincorporated herein by reference.

The material body 11 is made of a soft material that is compatible withthe electrode array body 10. In a preferred embodiment the body 11 madeof silicone having hardness of about 50 or less on the Shore A scale asmeasured with a durometer. In an alternate embodiment the hardness isabout 25 or less on the Shore A scale as measured with a durometer.

FIG. 38 depicts a cross-sectional view of the flexible circuit array 10being enveloped within an insulating material 11. The figure shows howthe edges of the material body 11 are lifted off due to the contractedradius. The electrode array 10 preferably also contains a fold A betweenthe cable 12 and the electrode array 10. The angle of the fold A securesa relief of the implanted material.

FIG. 39 depicts a cross-sectional view of the flexible circuit array 10being enveloped within an insulating material 11 with open electrodes 13and the material 11 between the electrodes 13. This embodiment also hasrelief between the body 10 and the retina.

FIG. 40 depicts a cross-sectional view of the flexible circuit array 10being partially enveloped within an insulating material 11 with openelectrodes 13. This is another embodiment wherein the electrodes 13 arenot separated by the material 11 but the material 11 is extended so thatthe electrodes 13 are prevented from directly contacting the retina.

FIG. 41 depicts a cross-sectional view of the flexible circuit array 10being enveloped within an insulating material 11 with electrodes 13 onthe surface of the material 11. This is a further embodiment with theelectrode 13 on the surface of the material 11, preferably silicone. Theembodiments shown in FIGS. 39, 40, and 41 show a preferred body 11containing silicone with the edges being lifted off from the retina dueto contracted radius of the silicone body 11.

FIG. 42 depicts a cross-sectional view of the flexible circuit array 10being enveloped within an insulating material 11 with electrodes 13 onthe surface of the material 11 inside the eye with an angle K in thefold of the flexible circuit cable 12 and a fold A between the circuitelectrode array 10 and the flexible circuit cable 12. The material 11and electrode array body 10 are in intimate contact with retina R. Thesurface of electrode array body 10 in contact with retina R is a curvedsurface having edges with a contracted radius compared to the sphericalcurvature of retina R to minimize stress concentrations therein.Further, the decreasing radius of spherical curvature of material 11near its edge forms edge relief that causes the edges of the body 11 tolift off the surface of retina R, eliminating stress concentrations. Theedges of body 11 are strongly lifted off due to the contracted radius ofthe body 11. The edge of body 11 has a rounded edge eliminating stressand cutting of retina R.

FIG. 43 shows a part of the FIG. 42 enlarged showing the electrode array10 and the electrodes 13 enveloped by the polymer material, preferablysilicone 11 being attached to the retina R.

The electrode array 10 embedded in or enveloped by the polymer material,preferably silicone 11 can be preferably produced through the followingsteps. The soft polymer material which contains silicone is molded intothe designed shape and partially hardened. The electrode array 10 whichpreferably contains polyimide is introduced and positioned in thepartially hardened soft polymer containing silicone. Finally, the softpolymer 11 containing silicone is fully hardened in the designed shapeenveloping the electrode array 10. The polymer body 11 has a shape witha contracted radius compared with the retina R so that the edges of thebody 11 lift off from the retina R.

FIG. 44 shows the flexible circuit electrode array prior to folding andattaching the array to the electronics package 14. At one end of theflexible circuit cable 12 is an interconnection pad 52 for connection tothe electronics package 14. At the other end of the flexible circuitcable 12 is the flexible circuit electrode array 10. Further, a point 24is provided at the end of the flexible circuit electrode array 10. Theflexible circuit cable 12 is formed in a dog leg pattern so than when itis folded at fold 48 it effectively forms a straight flexible circuitcable 12 with a narrower portion at the fold 48 for passing through thesclerotomy.

FIG. 45 shows the flexible circuit electrode array after the flexiblecircuit cable 12 is folded at the fold 48 to form a narrowed section.The flexible circuit cable 12 may include a twist or tube shape as well.With a retinal prosthesis as shown in FIG. 1, the bond pad 52 forconnection to the electronics package 14 and the flexible circuitelectrode array 10 are on opposite side of the flexible circuit. Thisrequires patterning, in some manner, both the base polymer layer and thetop polymer layer. By folding the flexible circuit cable 12 of theflexible circuit electrode array 10, the openings for the bond pad 52and the electrodes are on the top polymer layer and only the top polymerlayer needs to be patterned. Further, a point 24 is provided at the endof the flexible circuit electrode array 10. The point 24 shown in FIGS.2 and 3 is formed throughout the whole thickness of the array. The arraymay contain at least one bottom layer containing at least one polymer,copolymer, blockcopolymer or mixtures thereof and at least one top layercontaining at least one polymer, copolymer, blockcopolymer or mixturesthereof. The polymer may be polyimide, silicone, PEEK polymer, a repeatunit that comprises ofoxy-1,4-phenylenoeoxy-1,4-phenylene-carbonyl-1,4-phenylene, parylene ormixtures thereof.

Also, since the narrowed portion of the flexible circuit cable 12pierces the sclera, shoulders formed by opposite ends of the narrowedportion help prevent the flexible circuit cable 12 from moving throughthe sclera. It may be further advantageous to add ribs or bumps ofsilicone or similar material to the shoulders to further prevent theflexible circuit cable 12 from moving through the sclera.

Further it is advantageous to provide a suture tab 56 in the flexiblecircuit body near the electronics package to prevent any movement in theelectronics package from being transmitted to the flexible circuitelectrode array 10. Alternatively, a segment of the flexible circuitcable 12 can be reinforced to permit it to be secured directly with asuture. The retina tack (not shown) is placed through an attachmentpoint 54 to hold the flexible circuit electrode array 10 to the retina.A stress relief 55 can be made of a softer polymer than the flexiblecircuit 1.

FIG. 46 provides a cross-sectional view of a preferred embodiment of theeye 2 with a retinal implant 19 placed subretinally. The currentinvention involves the use of an electronic device, a retinal implant 19that is capable of mimicking the signals that would be produced by anormal inner retinal photoreceptor layer. When the device is implantedsubretinally between the inner and outer retinal layers, it willstimulate the inner layer to provide significantly useful formed visionto a patient who's eye no longer reacts to normal incident light on theretina 20. Patient's having a variety of retinal diseases that causevision loss or blindness by destruction of the vascular layers of theeye, including the choroid, choriocapillaris, and the outer retinallayers, including Bruch's membrane and retinal pigment epithelium. Lossof these layers is followed by degeneration of the outer portion of theinner retina, beginning with the photoreceptor layer. The inner retina,composed of the outer nuclear, outer plexiform, inner nuclear, innerplexiform, ganglion cell and nerve fiber layers, may remain functional.Functioning of the inner retina allows electrical stimulation of thisstructure to produce sensations of light or even vision.

The biocompatible retinal implant 19 is attached by an electricallyconductive cable or lead wire 25 that is also biocompatible, to acontrol electronics 14 package that contains suitable electronics togenerate an electrical signal that is transmitted along a lead wire 25to the retinal implant, which stimulates the retina 11. The lead wire 25passes transretinally through retinal incision 13 and enters thevitreous cavity 9. The lead wire 25 then passes transsclera at scleraincision 13 that passes through the sclera at a location near the frontof the eye where there is no retina 11.

The eye 2 has a cornea 4, lens 8, and vitreous cavity 9 through whichlight normally passes, prior to striking the retina 11 and causingvision. The eye 2 has an outer layer, called the sclera 6, and anutrient rich layer, called the choroid 18, that is located between theretina 11 and the sclera 6.

In a preferred embodiment, the retinal implant 20 is locatedsubretinally near the fovea 15 to provide good electrical contactbetween the retinal implant 19 and the retina 11. The lead wire 25,which is attached to the retinal implant 19, proceeds transretinallythrough retina 11 via retinal incision 23. Passing the lead wire intothe vitreous cavity 9 via the retinal incision 23 avoids disrupting thedelicate choroid 17, and thereby avoids interfering with the supply ofnutrients to the retina 11. The lead wire 25 passes through the vitreouscavity to a point near the front of the eye 2 where it traversestranssclera via an incision 13 through the sclera 6 at a point where theretina 11 and choroid 17 are not present, thereby further avoidingdisruption to the blood supply, oxygen, and nutrients that are needed tosustain the retina 11. While the choroid 17 does extend to this regionof the eye near the lens 8, called the pars plana, choroid 17 bleedingwill not damage the retina 11, and is far less likely to spread to thecentral retina 11, called the macula, which is the area of mostsensitive vision, while choroid 17 bleeding under the retina 11 cantrack along the retina 11 and end up damaging the macular region nearthe fovea 19 of the retina 11.

The control electronics 14 are located outside the eye 2 and areattached to lead wire 25. The control electronics 14 are preferablyattached to the sclera 6 by sutures. In alternative embodiments, thecontrol electronics 14 are located distant from the eye 2.

A perspective cross-sectional view of the retina and outer wall of theeye is presented in FIG. 47. Moving from the inside of the eye outward,the structure of the eye is encountered as follows: internal limitingmembrane 51, axons 53, ganglion and amacrine cell layer 55, innerplexiform 57, inner nuclear layer 58, outer plexiform layer 60, bipolarcell layer 62, photoreceptor cell layer 64, retinal pigment epithelium68, Bruck's membrane 70, choriocapillaris 72, choroid 74, and the outercoat or sclera 76.

The inner retina 78 is generally the structures from the internallimiting membrane 50 to the photoreceptor cell layer 64. The outerretinal layer is the retinal pigment epithelium 68 and Bruck's membrane70.

A subretinal implant position 80 is located between the photoreceptorcell layer 64 and the retinal pigment epithelium 68. In a preferredembodiment, the retinal implant 66 is surgically implanted in thesubretinal implant position 80.

In a preferred embodiment, the retinal implant 66 is biocompatible andcontains a number of arrayed electrodes 84, which are electricallystimulated by an outside source to stimulate the inner retinal layer 78,thereby to provide significantly useful formed vision. It is preferredthat the electrodes 84 are located on the surface of the retinal implant66 that faces the front of the eye, to stimulate the inner retinal layer78.

A cross-sectional view of the eye 102 and retinal implant 132 ispresented in FIG. 48. In this embodiment of the invention, drugs aredelivered by transfer from drug reservoir 130 to retinal implant 132,where the drugs are released subretinally for treatment of the tissue ofthe eye 2 and especially the retinal tissue. This device is particularlyadvantageous for treatment of chronic issues. A further advantage isthat the quantity of drugs required and released to the eye is minimizedby releasing the drugs in near proximity to the area of the eye 102 thatrequires treatment.

In a preferred embodiment, the drugs are transferred from drug reservoir130 via delivery conduit 128, which is preferably a tube, to retinalimplant 132. While the drugs may be pumped or delivered by other knownmeans, it is preferable that they be delivered electrophoretically.

The structure of the eye 2, as shown in FIG. 48, presents a cornea 104at the front of the eye with a lens 108 behind. The sclera 106 is on theoutside of the eye and the choroid 118 is inside the eye 2 between theretina 112 and sclera 106.

The retinal implant 132 is implanted subretinally, preferably near theback of the eye. It is shown near the fovea 113, in FIG. 48, but may belocated at other subretinal locations, as desired. The drug deliveryconduit 128 connects the retinal implant 132 with the drug reservoir130. The conduit 128 passes transretinally through retinal incision 124and enters the vitreous cavity 110. The conduit 128 then passestranssclera at sclera incision 114 that passes through the sclera at alocation near the front of the eye where there is no retina 112, therebyavoiding damage to the nutrient rich choroid 118 and avoiding disruptionof the blood supply to the retina 112.

An alternative embodiment of a retinal implant to enable visionrestoration is presented in FIG. 49, wherein a cross-section of the eyeis presented showing the lens 208, retina 212, sclera 206, and fovea213. U.S. Pat. No. 5,935,155, issued to Humayun, et al., the '155patent, describes a similar visual prosthesis and method of use. In thisembodiment, the retinal implant 220 is implanted subretinally. A primarycoil 232 is located preferably either in an eyeglass lens frame or in asoft contact lens. This coil 232 is used to inductively couple the radiofrequency encoded image signal to the secondary coil 230 that, in thisembodiment, is implanted behind the iris of the eye. The controlelectronics 222 is placed in a hermetically sealed package and iscoupled to a secondary coil 230 by a coil lead 223 that pierces thesclera 206 at a point near the lens 208 where there is no retina 212.The control electronics 222 is attached to the outside of the sclera206. A lead wire 226 coupling the control electronics 222 to the retinalimplant 220 passes transsclera at a point where there is no retina,preferably near the lens 208. The lead wire 226 passes inside the eye,preferably along the interior wall of the eye, and pierces the retina topass transretinal to couple the control electronics 222 to the retinalimplant 220. This invention is an improvement over that disclosed by the'155 patent because the retinal implant is subretinal rather thanepiretinal, thereby facilitating stimulation of the retinal tissue.

A further alternative embodiment of a retinal implant to enable visionrestoration is presented in FIG. 50. The '155 patent discloses a similarinvention, wherein the retinal implant 220 is placed subretinally. Inthis embodiment, the secondary 230 is attached to the sclera 206 insteadof being implanted within the eye. As with the control electronics 222,the attachment of the secondary coil 230 to the sclera 206 may be bysuturing or other appropriate means, as discussed in the '155 patent. Inthis way, only the lead wire 226 which attaches the control electronics222 to the retinal implant 220 mounted subretinally below retina 212 isrequired to pierce the sclera 206. The extra-ocular attachment of thecontrol electronics 222 allows increased access to this circuitry thateases the replacement or updating of these components.

FIG. 51 presents a perspective cross-sectional view of the retina andouter wall of the eye. The tissue layers from the inside of the eyeoutward are the internal limiting membrane 150, axons 152, ganglion andamacrine cell layer 154, inner plexiform 156, inner nuclear layer 158,outer plexiform layer 160, bipolar cell layer 162, photoreceptor celllayer 164, retinal pigment epithelium 168, Bruck's membrane 170,choriocapillaris 172, choroid 174, and sclera 176.

The inner retinal layer 178 is comprised of tissue from the internallimiting membrane 150 to the photoreceptor cell layer 164. The outerretinal layer 182 consists of the retinal pigment epithelium 168 andBruck's membrane 170.

Between the inner retinal layer 178 and outer retinal layer 182, is thesubretinal implant position 180 in which retinal implant 186 issurgically located.

The retinal implant contains a number of orifices 188 through with thedrug is released into the surrounding retinal tissue. The orifices 188are preferably uniformly presented on both the inner and outer surfacesas well as on the edges of the retinal implant 186. However, theorifices 188 may be preferentially oriented in the retinal implant 186to selectively release the drug on or near a desired tissue or location.

A fully functional and long-lasting device, composed of the implant andexternal system, is shown in FIG. 52. There is an extra-ocularelectronics package and secondary coil connected to a thin filmelectrode array that runs through a pars plana incision into the eyewhere the array is tacked onto the retina or placed subretinally througha retinotomy.

The retinal electrophysiology and human clinical testing are designed toprovide valuable information required to make device developmentdecisions. In some cases, device performance is limited by physical andelectrical constraints—i.e. material charge density limits or voltagelimits in today's integrated circuit technology. In other cases it islimited by the biology—i.e. tissue damage tolerance evaluated above,retinal biology, or eye movements.

Multi-electrode array recordings will allow us to measure thresholds foractivation of single or larger collections of ganglion cells.Preliminary experiments have shown that threshold stimulation using10-15 μm electrode diameters activates one or a few ganglion cellslocated within 60 μm of the stimulation site. By incorporating SecondSight manufactured electrode arrays with different sized electrodes intothe Salk Institute's multi-electrode recording system, it will be ableto record ganglion cell responses to stimulation with a wide range ofstimulating electrode diameters 5-500 μm.

The literature analysis of charge thresholds shown in FIG. 56 suggeststhat with decreasing electrode size, the required charge density doesnot significantly increase. The multi-electrode experiments indegenerate retina further show that electrodes with diameters of 10-20μm reliably stimulate individual ganglion cells in normal and degeneraterat retina at charge densities below 0.2 mC/cm². Thus, stimulation withsmall-diameter electrodes is likely to be both safe and effective whenusing platinum gray electrodes. The electrode spacing is in the 5-500 μmrange.

The simultaneous stimulation of two or more very small electrodes spaced60 μm apart results in independent activation of ganglion cells neareach stimulation site. Increasing the number of place-pitch steps afactor of 2-9× over single electrodes available to cochlear implantlisteners.

The proportion of the total current directed to each electrode will varybetween p=1 only the first electrode stimulated to p=0 only the secondof the two electrodes stimulated. If both electrodes are stimulated withequal amounts of current, normalized for electrode sensitivity,presented to each electrode then, p=0.5. On each trial, multiple stimulip=1, p=0.5 or p=0 separated in time will be presented in random order,and the subject asked to press a key every time the stimulus appearsfurther to the right than the previous one assuming laterally adjacentelectrodes. If this experiment results in the perception of threephosphenes that are distinctly located in space, then a secondexperiment will be conducted where more discrete levels for p areselected. Analysis of the function relating current ratio (p) to theperceived spatial position will be used to determine whether currentsteering can produce reliable shifts in the position of the resultingphosphene and how many intervening ‘virtual electrodes’ can be produced.

For an epiretinal prosthesis, the size of the electrode array isdictated by surgical concerns to about 5×6 mm. This is the area whichfits comfortably between the large ‘arcade’ blood vessels which surroundthe macula. If an array were larger than this, blood flow to the distantretina might be compromised. It is currently unknown how large asubretinal array can be, but surgical limitations may limit its size tosomething similar.

The size of the overall array and the electrode center-to-center spacingdictate how many electrodes will fit in the given area. Obviously, theelectrode size diameter must also be smaller than the center-to-centerspacing.

This design essentially employs an electronics package that supports 250channels with a 1:4 electrode selector that is integrated into thearray. Thus each driver can drive up to 4 electrodes at a time resultingin an implant that may support up to 1,000 electrodes, if necessary.FIG. 53 shows the epiretinal version, but the subretinal version will besimilar with the cable passing through a retinotomy and thede-multiplexer inverted so that the electrodes face the retina. Thereare approximately 250 lines on the thin film cable running down thechannel selector that is integrated onto the array.

If between 60 and 250 electrodes are needed, then the following threecomponent technologies will be required:

(1) A thin-film array technology of sufficient density to permit routingto 250 electrodes. Sufficient improvements in density could come fromprocess improvements mask and alignment resolution and an additionalmetal layer for the cable.

(2) An electronics package with up to 300 vias/cm² instead of the 100vias/cm² that the implant contains.

(3) An ASIC driver for 250 individually addressable channels. This willbe achieved through emerging packaging approaches and a change in thechip fabrication process to 0.6 um, 0.35 um or possibly smaller.

If more than 250 electrodes are needed, then three additional componenttechnologies will be required:

(4) Development of an integrated array and channel selector IACS,including a means of forming the array. The IACS will contain a 1-to-4channel demultiplexer and will have integrated electronics on the ‘back’flat surface and electrodes on the ‘front’ formed surface. It isanticipated that the IACS will be made from silicon using a combinationof standard micro-fabrication procedures to integrate the requiredelectrical components and custom MEMS engineering to shape the arrayportion and provide electrical feedthroughs to the electrodes.

(5) Development of a low-profile package to protect the IACS. The IACSwill be interconnected to the thin flexible cable described above usinga platinum conductor technique developed during the first BRP period,but the IACS device itself needs to be packaged as it is well known thatsilicon degrades in the human body. It is not possible to put a massivepackage on the delicate retina, and so a thin film package <10 um is thepreferred solution. In addition, the film can be patterned selectivelyto expose electrical contacts vias where required. Testing of this thinfilm package has demonstrated via densities of 25 vias/mm² and lifetimesin excess of 5 years in saline.

(6) Modifications to the 250 stimulator in order to support electrodeselection. Control lines and circuits will be added to the 250-channeldriver chip to control the IACS.

The implant is attached to the sclera using a 240 band and two sutures,and the electrode array and cable introduced into the eye through anenlarged supero-temporal sclerotomy. For an epiretinal approach theelectrode array is tacked over the area centralis, while for asubretinal approach the array is inserted under the area centralisthrough a retinotomy. The sclerotomies and conjuctiva are closed andsteroids and antibiotics are injected. The animals are providedanalgesia for 48 hours post-operatively. Prophylactic antibiotics andsystemic steroid are provided over 2 weeks postoperative.

Electrophysiology—Patch pipettes will be used to make small holes in theinner limiting membrane and ganglion cells will be targeted under visualcontrol. Light responses will be used to assign the targeted cell to aknown ganglion cell type. Spiking will be recorded with a cell-attachedpatch electrode 5-6 MΩ, filled with superfusate. Excitatory andinhibitory input currents will be measured with whole-cell patch clampelectrodes 6-7 MΩ.

Distinguishing neural activity from stimulus artifact: The response topulses of electrical current consists of large transient currents (FIG.54 a, horizontal arrows) that are temporally correlated with the onsetand offset of both phases of the stimulus pulse cathodic and anodic. Aseries of biphasic waveforms (asterisks) follow the large transientcurrents. These biphasic waveforms have similar magnitudes and kineticsto light-elicited action potentials

(FIG. 54 inset). FIG. 54: Stimulus pulses elicit 2 phases of neuronalspikes. (a) Biphasic stimulus pulse consisting of 3 ms cathodic phase, 5ms inter-phase interval and 3 ms anodic phase timing at top elicits 5biphasic waveforms (asterisks) in retinal ganglion cell. (b) TTXeliminates all biphasic waveforms indicating they are neuronal spikes.TTX also modulates the response in the region immediately following theonset of the cathodic pulse gray box. Subtraction of the TTX responsefrom control indicates a single biphasic waveform (inset) that hassimilar kinetics and magnitude to the average light-elicited spike(dotted).

Tetrodotoxin (TTX), a blocker of neuronal spiking, eliminates thebiphasic waveforms (n=5/5), confirming that they were conventionalvoltage-gated Na⁺ spikes.

This suggests that one or more spikes are buried within this transientcurrent. To reveal the spike(s) it is reasoned that the response in TTXdid not contain neural activity and was therefore mainly electricalartifact generated by the stimulus pulse. Subtraction of the electricalartifact TTX response from the control response reveals an additionalpulse-elicited spike (inset, solid trace, n=5/5). The waveform of thisspike is nearly identical to the average light-elicited spike for thiscell (inset, dotted trace). It is referred to this single spike as the‘early-phase’ spike and referred to the subsequent series of multiplespikes biphasic waveforms as ‘late-phase’ spikes. Similar results arefound in all ganglion cell types of the rabbit retina. The onset of theTTX-extracted pulse-elicited spike closely follows the onset of thecathodic pulse (mean=580 μs, range=400-680 μs, n=5). Without TTX, it isdifficult to precisely determine the onset of the elicited spike, butcomparison of control records in 5 TTX and 15 non-TTX experiments aresimilar, providing additional support that the elicited spike closelyand consistently follows the stimulus pulse onset.

The multi-electrode retinal system consists of the following components:(1) a rectangular two-dimensional array of 512 planar microelectrodeswith a sensitive area of 1.7 mm² in total, or an array of 61 electrodesarranged hexagonally, with an area of 0.25 mm². The preliminary datawere gathered using the 61-electrode array. Each microfabricatedplatinum electrode is 5-15 microns in diameter and theelectrode-electrode spacing is 30-60 microns. (2) custom-designedintegrated circuits to pass current through the electrodes and AC coupletheir output signals; (3) integrated circuits to amplify, band-passfilter and multiplex the recorded signals; (4) a data acquisitionsystem; and (5) data processing software.

Live retina is placed in a chamber, ganglion cell side down, on top ofthe array. The tissue is bathed continuously with a flow of oxygenatedphysiological saline solution, which allows the retina to be kept alivefor up to 12 hours. The raw data recorded are the electrode voltagesignals, digitized at 20 kHz: typically, each electrode picks up spikesfrom several neurons, and each neuron produces signals on severalelectrodes. For electrical stimulation, rectangular charge-balancedcurrent pulses are applied through one or multiple electrodes; forvisual stimulation, white noise or other stimuli are presented on ascreen and optically focused on the retina. Extracellular spikes areidentified based on their characteristic bi- or triphasic shape;electrically evoked spikes are by definition time-locked to the stimuluspulse by a latency of 0.2-15 milliseconds. Signals from all electrodesare stored for off-line analysis.

To distinguish neural responses from the electrical artifact, a novelmethod of threshold artifact subtraction will be employed, allowingevoked spikes to be recorded at latencies of a few hundred μs. It takesadvantage of the fact that near threshold some stimulation trials willresult in evoked spikes and some will fail to evoke responses.Subtracting the failures from the successful stimulations eliminates theartifact and cleanly reveals the recorded ganglion cell spike (see FIG.55). FIG. 55 shows: Top example of a spontaneous spike (gray arrow) andan evoked spike (black arrow) which was hidden in the electricalartifact and required artifact subtraction to reveal. Bottom example isthe same stimulation experiment at an expanded scale. A superposition ofseveral stimulation trials is shown, some of which evoked a spike(arrow). Bottom trace is the digital subtraction of averaged traces fromtrials with and without an evoked spike. Vertical dashed line indicatesstimulation onset. Latency=0.25 ms. Inset shows the spontaneous spike atthe same scale for comparison.

Two interval forced choice technique subjects are presented with twointervals denoted by computer beeps, which contain different stimuli,and are forced to choose the stimulation interval, via a key-press thatcontains the brighter stimulus. This approach avoids response biasesbecause if the stimuli presented in the two intervals are perceptuallyindistinguishable, then subjects will perform at chance in respondingwhich interval contained the brighter stimulus. A correct response willbe given auditory feedback with a beep.

The threshold is the stimulation intensity at which the subject performsat 50% correct, corrected for the false alarm rate in the case of theyes-no paradigm) and is 80% correct performance in the case of theprocedure. Errors in the threshold estimation are characterized by the90% confidence interval in which the “true” threshold value will fall.

Brightness or size matching—The subject is presented with two intervals:one containing a “standard” stimulation pulse whose parameters willremain fixed throughout the experiment and a second containing a“matching” stimulation pulse produced using different parameters. Thesubject selects the interval that contained the brighter stimulus. Ifthey report that the matching pulse was brighter, its intensity will bereduced on the next trial. If they report that the standard pulse wasbrighter, the matching pulse's intensity will be increased on the nexttrial. The technique described above will be used to fit the data andthe 50% correct value is considered the point of “subjective equality”.

The height of the electrodes from the retinal surface can be measured byusing optical coherence tomography (OCT). A cross-sectional image of theretina is taken using the optical backscattering of light. The opaqueplatinum electrodes cast broad shadows and the height of these shadowsfrom the retinal surface can be measured. An image processing programhas been developed that loads OCT images, determines the OCTpixel-micron conversion factor, identifies individual electrodes andmeasures electrode height and retinal thickness.

Eye movement recording—A video-based eye tracking system (ArringtonResearch) is used to record eye position, including nystagmus. Becausethe pupil position of blind subjects cannot be calibrated to theposition of visual targets using usual techniques, a novel calibrationtechnique is developed that maps the pupil position to the location oftactile calibration points across the visual field.

To determine the smallest safe electrode size for a high resolutionprosthetic, it is necessary to know whether perceptual thresholds forelectrical stimulation are determined by the amount of charge or thecharge density. If thresholds are determined by the total charge, thenthe small electrodes required to increase spatial resolution are likelyto result in charge densities that reach unacceptable levels. Chargethresholds generally decrease with electrode size. The solid line inFIG. 56 represents a line of constant charge density (0.2 mC/cm²) whichyields a correlation coefficient R²=0.75. While larger electrodesclearly require higher charge injection for successful stimulation, thedata points lie close to the line denoting constant charge density.These stimulation experiments in isolated retina show that spikes can bereadily elicited in ganglion cells, even with very small electrodes,without exceeding the charge density limit for platinum gray electrodes(1.0 mC/cm²). Solid circles denote the average data from 3 humansubjects tested using 250 μm and 500 μm electrodes (means±standarddeviation).

Recent threshold measurements in transgenic rats with severelydegenerated retinas showed that spike thresholds in degenerated retinaare not different from those of normal retina (FIG. 57). These findingssuggest that very small electrodes can directly stimulate ganglioncells. Avarage threshold currents in normal (dark bars) and degenerated(light bars) retinal using 0.1 ms pulses (±SEM). Three electrodediameter ranges are shown. Number indicate numbers of stimulated cells.To verify this, blockers of synaptic transmission were added to theperfusion. Spike shapes, latencies, and response rates were unchanged in9 cells tested (FIG. 58), indicating that ganglion cells were activateddirectly and not by presynaptic input from bipolar cells. Response to 10stimulus pulses in a cell with spikes at latency 5.5 ms in rat retina.Bottom: A combination of glutamate receptor antagonists was added to theperfusion solution. The finding that thresholds are determined by chargedensity (FIG. 56), and our demonstration that these results also holdfor degenerated retina (FIG. 58) suggest that it may indeed be possibleto significantly reduce electrode sizes.

Three human subjects were implanted with a checkerboard style arraycontaining electrodes alternating between 250 μm and 500 μm to determineif these electrode sizes resulted in different thresholds. Thresholdswere measured using a biphasic charge balanced pulse 0.975 ms cathodic,0.975 ms interpulse delay, 0.975 ms anodic. The checkerboard arrangementwithin individual subjects minimized the effects of any tilt of thearray on the retinal surface or any differences between subjects intheir state of retinal degeneration. A significant increase was observedin the amount of charge required to elicit a percept for the largerelectrode size (FIG. 56, filled circles) as would be expected ifthresholds were related to charge density.

FIG. 59 shows the correlation between height and electrical stimulationthreshold in these 4 subjects. Close proximity of the array to theretinal surface yields lower stimulation thresholds. Thus, the electrodearray should lie as close to the retinal surface as possible. Data inanimals has consistently shown that the electrode surface is within 50μm of the retina.

FIG. 60 shows the ability of two subjects to discriminate between asingle stimulated electrode and a pair of stimulated electrodes. Thecurrents needed to produce equal apparent brightness for the singlepulse and the pulse pair were equalized prior to the start of theexperiment and then the current was jittered on each trial to preventsubjects from using small brightness changes as a cue to perform thetask. FIG. 60 shows a two-point discrimination performance. The x-axisrepresents the distance on the retina between the stimulated electrodes(1 mm on the retina is equivalent to 3° of visual angle). Performance isshown for two subjects; performance for horizontally (solid line) andvertically (dashed lines) aligned electrodes is shown separately. Errorbars represent binominal error estimates of the mean.

Performance for adjacent electrodes 0.8, 1.6, and 2.4 mm apart is shownfor both subjects. The subjects performed significantly better thanchance (50% correct) (p<0.05, 1-tailed t-test) for all electrodeseparations. A pair of pulses on two different electrodes was presented,separated by a 300 msec time interval and subjects were asked to reportif the second pulse was either above/below or left/right of the first(FIG. 61). The subjects' performance was well above chance, though inthe case of Subject S5, performance was at chance for left/rightdiscriminations. FIG. 61 shows a relative position performance.Performance is shown for two subjects; and performance for horizontal(solid line) and vertical (dashed line) discriminations are shownseparately. Error bars represent binominal error estimates of the meanand are smaller that the symbols.

A randomly chosen electrode was then stimulated with a single 0.975 mssupra-threshold pulse and the subject positioned a second magnetic tokenin the perceived location of the phosphene. Each electrode wasstimulated twelve times. The average position of the phosphenecorresponding to each electrode, relative to (0,0), was calculated. Theperceived depths of the phosphenes elicited by each electrode weremeasured in a separate study. The results of these experiments (FIG. 62)provide evidence that each stimulated electrode consistently produces aphosphene in a specific location, and that the total visual area coveredby the electrodes roughly corresponds to the physical size of the arrayprojected into visual space. Spatial location of phosphenes associatedwith individual electrodes. This spatial map shows that each electrodeproduces a phosphene in a specific location, and that the visual anglespanned by these phosphenes is consistent with the physical size of thearray.

The spatial spread of electrical activation was measured in normal ratretina using a hexagonal multi-electrode array (FIG. 63). The recordingelectrode was always in the center of the array. When stimulation was atthe recording electrode (left panel) threshold was 0.9 μA. When a singleadjacent electrode (60 μm distant from the recording electrode) was usedfor stimulation (right panel), about three times more current was neededcompared to stimulation at the recording electrode. This suggests that,with small electrodes (6 μm-19 μm in size), the effects of electricalstimulation tend to be narrowly focused spatially. FIG. 63 shows spikethresholds for two stimulation configurations. Filled circles indicateactive electrode used for stimulation, open circles denote unusedelectrodes. The recording electrode (R) was always in the center.Threshold currents are shown as averages+/−SEM in 8 cells. Electrodeswere 60 μm apart.

The effect of stimulating seven electrodes simultaneously was examinedusing a multi-electrode array consisting of 10 μm electrodes separatedby 60 μm. Suprathreshold pulses (0.8 μA, 0.1 msec duration) werestimulated and recorded using 7 electrodes in this array. Stimulatingeach electrode individually evoked spikes that could be recorded at thestimulating electrode. Then all 7 electrodes were stimulated andrecorded simultaneously (FIG. 64). Simultaneous stimulation evoked sevendistinct responses on the seven spatially disparate electrodes. Theseresponses did not differ from those recorded when stimulatedindividually. Adjacent electrodes did not influence each other duringsimultaneous stimulation. Spikes recorded on one electrode were, atmost, reflected as very small deflections on other electrodes. Thisprovides further evidence (in normal retina) that 60 μm is sufficientspacing to avoid electrode interactions using small stimulatingelectrodes.

FIG. 65 shows a fundus photo and flourescein angiogram after 3 month ofthe preferred flexible circuit 1 implant in a rabbit. It is shown thatthe point 24 of the flexible circuit 1 cuts the retina as it isinserted. 15 rabbits were chronically implanted for over three monthseach with polyimide flexible circuit 1 which were from 0.3 mm to 0.7 mm,preferably about 0.5 mm wide and from 3.5 mm to 4.5 mm, preferably about4 mm long using the preferred trans-retinal surgical approach whichincluded laser treatment around the retinotomy site. The flexiblecircuit 1 were inserted under the retina and left with a portion of theflexible circuit cable 12 sticking out into the vitreous. In an actualdevice, according the present invention, the flex circuit cable 12 ofFIG. 65 would be attached to an electronics package 14 as describedabove. The polyimide models were inserted under the retina and left witha portion of the model sticking out into the vitreous. It was notobserved any retinal detachment, proliferate retinopathy or any othersurgical complication in any of these animals over the 3-4 month implantperiods (FIG. 65).

Longer duration pulses also stimulated ganglion cells, but in additionstimulated other cell types deeper in the retina. Patch clampmeasurement of input currents to ganglion cells allowed us to directlydetermine if other retinal cell types are activated by electricalstimulation and affect the ganglion cell response. Excitatory inputcurrents indicate activation of presynaptic excitatory cells (mostlikely bipolars) and measurement of inhibitory currents indicatesactivation of presynaptic inhibitory cells (most likely amacrine cells).Long duration (1 ms) pulses elicited both excitatory and inhibitorycurrents (FIG. 66).

Spatial spread of activation was measured by positioning the stimulatingelectrode at different distances from the ganglion cell soma (FIG. 65).The largest excitatory currents were elicited when the stimulatingelectrode was placed directly over the soma. Moving the stimulatingelectrode away from the soma caused a consistent decrease in the maximumamplitude of excitation (compare maximum amplitudes of excitation in theleft panel vs. the middle and right panels). Surprisingly, the largestinhibitory current was generated when the stimulating electrode was notdirectly over the soma (FIG. 66, middle panel). Even when thestimulating electrode was 125 μm from the soma, the inhibitory currentwas larger than when the stimulating electrode was directly over thesoma. Substantial inhibitory currents was at distances up to 225 μm fromthe soma. The peaks between inhibitory activity occur between and afterperiods of spiking. Scale bars: Vertical: 100 pA, 25 mV, Horizontal: 20ms; applies to all panels.

The temporal duration of inhibition varied as a function of the distancebetween stimulating electrode and soma. Inhibition persisted longer whenthe stimulating electrode was 75 μm from the soma, than at 0 or 125 μm.Thus, the strength and duration of inhibition are robust at a distanceof about 75 μm from the soma and decrease steadily as the distance fromthe soma increases beyond that. These findings suggest that longstimulus pulses generate a wave of activity that could inhibit ganglioncells' responses to subsequent pulses.

If ganglion cells could be stimulated directly without stimulating anyof the excitatory or inhibitory circuitry that modifies their responses,then their responses in space and time could be accurately controlled.The observation that excitatory input elicited (via bipolar cells) byelectrical stimulation function of pulse duration (longer durationpulses generate larger excitatory inputs (FIG. 67 Qa, n=2/2 cells))suggested that decreasing the pulse duration might reduce or eliminateexcitatory input to ganglion cells, and possibly reduce inhibitory inputas well.

Spikes produced by short pulses were measured by subtracting out thelarge electrical stimulation artifact, which was isolated by applying adrug (TTX) that blocks spiking activity (FIG. 67 b. The resulting trace(FIG. 67 c) provides a measure of the spiking activity of the cell andshort pulses only generate a single, early phase spike. This ability togenerate direct ganglion cell spiking was found consistently in 16cells. This suggests that short pulses directly stimulate ganglion cellsand avoid modification of their response by excitatory or inhibitoryinputs.

FIG. 68 shows example curves showing brightness ratings as a function ofstimulation intensity for S5 and S6. Brightness ratings were measured bypresenting each subject with an easily visible “standard pulse” (ratedby default as a “10”) and having the subject rate subsequently presentedpulses that varied in amplitude “20” if they were twice as bright as thestandard pulse, “5” if they were half as bright as the standard pulse,and so on. The standard pulse was presented in between each trial. Inthe case of normal vision, apparent brightness increases monotonicallybut compressively with luminance. It seems that apparent brightness alsoincreases monotonically but slightly compressively with stimulationamplitude.

Although the brightness rating ranges of these two subjects differ, theycan both identify different brightness levels with similar accuracy. Thenumber of brightness steps that subjects can identify can be calculatedfrom the standard deviation of their brightness ratings (standard errorsare shown in FIG. 68). These calculations suggest that Subject 5 canidentify 6 brightness levels and Subject 6 can identify 6.5 brightnesslevels with 95% accuracy.

The brightness functions of different electrodes using a two intervalbrightness matching technique were compared. In one of the two intervalssubjects were presented with a pulse on one electrode at a standardcurrent intensity. In the second of the two intervals (these twointervals were presented in a random order) subjects were presented witha pulse on a different test electrode. Subjects judged which of thepulses were brighter and the current intensity on the test electrode wasvaried to find the value where standard and test pulses appeared equallybright. This procedure was repeated for a range of current levels on thestandard electrode. FIG. 69 plots the test electrode current required tomatch the ‘standard’ electrode for 2 electrodes in two subjects. Thex-axis represents the current intensity on the standard electrode andthe y-axis represents current intensity on two test electrodes. A linearfit with zero intercept (shown with dashed lines) describes the datawell. These functions will allow us to match brightness acrosselectrodes so that objects will not change in their apparent brightnessas they move to a different position on the electrode array. It is alsopossible to indirectly measure the number of brightness steps thatsubjects can discriminate from these data based on the slopes of thebrightness matching function. These calculations suggest that subjectscan discriminate 6 brightness levels with 95% accuracy, similar to theestimate from brightness rating measurements.

Short duration stimulus pulses elicited a single spike per pulse(asterisks); spikes were phase locked to the stimulus (FIG. 70 a, top).Similar responses were observed in 12 cells at all frequencies tested(:>250 Hz; ganglion cells can generate light elicited spiking at ratesup to 250 Hz). This is demonstrated in FIG. 70 b. The time interval from1 ms before to 2 ms was extracted after each cathodic pulse and overlaidthese traces. These individual traces were extremely consistent.Comparison of these overlaid responses with responses using TTX (whichblocks spiking activity; dotted trace) indicates that each pulse elicitsa single spike with a very consistent phase lag.

It was possible to consistently generate one spike per pulse over a widerange of stimulus amplitudes, as shown in FIG. 70 c. The two columnsrepresent two different time scales. The left column indicates that atabove threshold levels, stimulus pulses elicited spikes, as shown by thesmall deflection in the stimulus artifact trace (vertical arrow, leftgray box). The threshold at which spiking occurred was determined bycomparing the shape of the early phase response to the shape of theresponse when spiking activity was blocked by TTX (FIG. 70 b). Thisearly phase response persisted for all stimulus levels above threshold.For this cell the threshold was around 100-120 μA. For the population(n=13), the mean threshold amplitude was 193±64 μA.

At higher amplitude levels, late phase spiking was elicited (FIG. 70 cright column, right gray box). For this cell late phase spiking wasobservable at stimulus amplitudes above 340 pA. Thus, late phase spikeswere not observed until stimulation levels were almost 2.8× thresholdamplitude.

Because short pulses enable us to elicit spikes in ganglion cells withsuch exquisite reliability, it is possible to mimic responses to lightstimuli with surprising accuracy. The spiking response was measured tothe flash of a small square of light and then constructed a series ofelectrical pulses that mimicked the light evoked spiking pattern. Thiselectrical pulse pattern produced a pattern of elicited spikes whosetemporal pattern precisely matched the pattern of light-elicited spikes.Jitter between individual light- and pulse-elicited spikes was less than0.5 ms. Different spike patterns (such as responses to changes in lightluminance levels) could also be replicated. These data were collected innormal rabbit retina. The short pulses can generate single ganglion cellspikes up to very high frequencies with multi-electrode recordings indegenerated rat retina. Rapid pulse pairs (200 Hz interval) evokedspikes with 99% reliability (71 spikes out of 72 pulse pairs; 3 ganglioncells). In another experiment, biphasic pulses were presented at 50 Hzfor several seconds. Single spikes were generated throughout thestimulation period with 94% reliability (656 spikes out of 689 pulses; 3cells). These results confirm that short electrical pulses can be usedto precisely control the spiking pattern of ganglion cells indegenerated retina.

The pulse frequency can be used to manipulate brightness in humansubjects. The first panel of FIG. 71 shows the current required to reachthreshold for a 200 ms interval of pulses as a function of frequency ofpulses in the interval. This typical example is from Subject 6. Thesecond panel re-plots these data to show the charge required to reachthreshold. The current needed to reach threshold decreases as a functionof pulse frequency; however the charge needed to reach thresholdincreases as a function of frequency.

As shown by the solid lines in FIG. 71 the data describing brightness asa function of frequency can be fit by the equations J=eP^(g) andC=epP^(g) where I is the current needed to reach threshold, C is thecharge needed to reach threshold, p is the pulse width, and e and g areexperimentally determined. Brightness was also measured as a function offrequency using a supra threshold brightness matching procedure.Suprathreshold curves followed a similar function as the thresholdcurves.

For a 200 msec pulse train the drop in the amount of current needed as afunction of frequency begins to asymptote at higher frequency levels.However, data with shorter pulse train intervals (not shown) suggeststhat this may be due to rapid adaptation effects, and for shorterbursts, rate coding may be possible using even very high frequencies.These data suggest that it is possible to use frequency to manipulatethe brightness of percepts. However, this will come at a cost as far ascharge efficiency is concerned. The decrease in charge efficiency as afunction of frequency is less severe for short (0.075) pulses than forlong (0.975) pulses (data not shown) suggesting that a frequency codingapproach to coding brightness in human subjects will most likely requirethe use of short pulses.

The invention relates to an implantable device to affect an eye, the eyehaving a retina, a sclera, and a vitreous cavity, said devicecomprising:

a retinal implant that is positioned subretinally;

said retinal implant comprising at least one electrode connected with astimulating source;

at least one connection with said stimulating source and with said atleast one electrode, wherein said connection is suitable to passtransretinally into the vitreous cavity of the eye;

said connection suitably designed to pass through the sclera at a pointwhere there is no retina; and

said stimulating source is suitable to be located outside the sclera.

The retinal implant is configured to enable electrical stimulation of aretina of an eye to produce artificial vision.

The stimulating source is comprised of a source of electrical signal.The connection is comprised of an electrical lead. At least oneelectrode that is configured to pass an electrical signal to the retina.The retinal implant that is positioned subretinally is suitable to bepositioned between the photoreceptor cell layer and the retinal pigmentepithelium. The stimulating source comprises electrical coupling with asecondary coil, which receives electromagnetic signals from a primarycoil, said primary coil located outside the sclera. The secondary coilis suitable to be located inside the eye. The secondary coil is suitableto be located outside the sclera.

The invention relates to an implantable device to deliver drugs to aneye, the eye having a retina, a sclera, and a vitreous cavity, saiddevice comprising:

a retinal implant that is positioned subretinally for drug release;

said retinal implant comprising a drug delivery device connected with adrug reservoir;

at least one connection between said drug reservoir and said retinalimplant, wherein said connection is suitable to pass transretinally intothe vitreous cavity of the eye;

said connection being suitable to pass through the sclera at a pointwhere there is no retina; and

said drug reservoir is located outside the eye.

The implantable device delivers the drugs electrophoretically. Theconnection comprises a tube. The retina additionally is comprised of aphotoreceptor cell layer and a retinal pigment epithelium wherein saidretinal implant that is positioned subretinally is suitable to bepositioned between the photoreceptor cell layer and the retinal pigmentepithelium.

The invention relates to an artificial retinal device to electricallystimulate a retina of an eye to produce artificial vision, the eyehaving a sclera, and a vitreous cavity, said artificial retinal devicecomprising:

a retinal implant that is positioned subretinally;

said retinal implant comprising at least one stimulating electrodeconnected with an electrical source that is located outside the eye;

at least one electrical lead connected with said electrical source andwith said at least one stimulating electrode, wherein said electricallead is suitable to pass transretinally into the vitreous cavity of theeye; and

said electrical lead passing through the sclera at a point where thereis no retina.

The electrical source is suitable to affix to the sclera of the eye withsutures. The electrodes are facing the retinal. The retina additionallyis comprised of a photoreceptor cell layer and a retinal pigmentepithelium wherein said retinal implant that is positioned subretinallyis suitable to be positioned between the photoreceptor cell layer andthe retinal pigment epithelium.

The invention relates to an implantable device drug delivery device todeliver drugs for treatment to affect an eye, the eye having a retina, asclera, and a vitreous cavity, said device comprising:

a retinal implant that is positioned subretinally;

said retinal implant comprising at least one orifice connected with adrug reservoir;

at least one delivery conduit connected with said drug reservoir andwith said at least one orifice, wherein said delivery conduit issuitable to pass transretinally into the vitreous cavity of the eye;

said delivery conduit suitably designed to pass through the sclera at apoint where there is no retina; and

said drug reservoir is suitable to be located outside the sclera.

The implant releases said drugs electrophoretically. The deliveryconduit is a tube that transfers said drugs from said drug reservoir tosaid retinal implant. The drug is suitable to stimulate living tissue.The retinal implant that is positioned subretinally is suitable to bepositioned between the photoreceptor cell layer and the retinal pigmentepithelium. The implantable device comprises an electrophoretic drugdelivery device. The retinal implant is configured to enable drugstimulation of a retina of an eye to produce artificial vision.

The invention relates to a method for producing an artificial retinaldevice suitable to electrically stimulate a retina of an eye to produceartificial vision, the eye having a sclera, and a vitreous cavity, saidmethod comprising the steps of:

selecting a biocompatible retinal implant;

placing at least one stimulating electrode in said retinal implant thatis suitable for electrically stimulating the retina;

connecting an electrical lead to said stimulating electrode;

adapting said electrical lead to pass transretinally into the vitreouscavity of the eye;

attaching said electrical lead to an electrical source that is locatedoutside the eye; and

passing said electrical lead through the sclera at a point where thereis no retina.

The invention relates to a method for producing artificial vision in aneye using an artificial retinal device, the eye having a sclera, aretina, and a vitreous cavity, wherein said artificial retinal devicecomprises a retinal implant further comprising at least one stimulatingelectrode in said retinal implant, said stimulating electrode connectedwith an electrical source, at least one electrical lead connected withsaid electrical source and said electrode, the method comprising thesteps of:

adapting said retinal implant to be positionable in the subretinalposition in the eye;

adapting said electrical lead to be suitable to pass transretinallythrough the retina of the eye into the vitreous cavity; and

adapting said electrical lead to be suitable to pass through the scleraat a point where there is no retina.

The method comprises the step of attaching said electrical source to thesclera by sutures.

The method further comprises the step of positioning said electrodes toface the retina.

The invention relates to a visual prosthesis, comprising:

means for perceiving a visual image where said means is suitable to belocated outside the eye of a user, said means producing a visual signaloutput in response thereto;

retinal tissue stimulation means adapted to be operatively attached to aretina of a user, where said retinal stimulation means is suitable to belocated below the retina of a user; and

wireless visual signal communication means for transmitting said visualsignal output to said retinal tissue stimulation means.

The invention relates to a method of at least partially restoring visionto a user who suffers from photoreceptor degenerative retinal conditionsof the eye, comprising the steps of:

perceiving a visual image and producing a visual signal output inresponse thereto;

wirelessly transmitting the visual signal output into the eye of a user;and

stimulating retinal tissue of the user by means of an electrode, that issuitable to be placed below the retina of a user, in accordance with thevisual signal output.

The invention relates to a flexible circuit electrode array comprising:

a polymer base layer;metal traces deposited on said polymer base layer, including electrodessuitable to stimulate neural tissue; andsaid polymer base layer and said metal traces are embedded in a bodyhaving a generally oval shape in the plane of the retina, said ovalshaped body being curved such that it substantially conforms to thespherical curvature of the retina of the recipient's eye.

The flexible circuit electrode array comprises at least one mountingaperture in said body for attaching the electrode array to the retinawith a tack. The oval shaped body has a radius of spherical curvature,which is smaller than the radius of the curvature of the eye. The ovalshaped body is made of a soft polymer containing silicone havinghardness of about 50 or less on the Shore A scale as measured with adurometer. The flexible circuit cable portion has an angle of about 45°to about 180°. The flexible circuit cable portion has a bend with anangle of about 60° to about 120°. The flexible circuit cable portion hasa bend with an angle of about 45° to about 180°. The flexible circuitcable portion has a bend with an angle of about 60° to about 120°. Theflexible circuit cable portion has a fold within the attached flexiblecircuit electrode array with an angle of about 1° to about 180°. Theflexible circuit cable portion has a fold within the attached flexiblecircuit electrode array with an angle of about 20° to about 90°. Theflexible circuit cable portion has a horizontal angle within theattached flexible circuit electrode array of about 1° to about 90°. Theflexible circuit cable portion has a horizontal angle within theattached flexible circuit electrode array of about 10° to about 45°. Theflexible circuit cable portion comprises at least one grooved or rippledpad for capturing a mattress suture. The flexible circuit electrodearray is positioned on the surface of the body having a generally ovalshape. The soft insulating material is positioned on the surface betweensaid electrodes. The film containing a soft polymer is applied on saidflexible circuit cable portion. The film containing a soft polymercontains silicone. The film containing a soft polymer comprises a ladderlike structure. The film containing a soft polymer contains beads and/orbumpers.

The invention relates to a method of making a flexible circuit electrodearray comprising:

depositing a polymer base layer;depositing metal on said polymer base layer;patterning said metal to form metal traces;depositing a polymer top layer on said polymer base layer and said metaltraces; andheating said flexible circuit electrode array in a mold to form a threedimensional shape in said flexible circuit electrode array.

The method further comprising the steps of heating said flexible circuitelectrode array in successively smaller molds. The step of depositingsaid polymer base layer and said polymer top layer is depositingpolyimide. The step of depositing said polymer base layer and saidpolymer top layer is depositing silicone. The step of depositing saidpolymer base layer and said polymer top layer is depositingfluoro-polymer. The method further comprising forming a twist in aflexible circuit cable portion of said flexible circuit electrode array.

Accordingly, what has been shown is improved methods of making a neuralelectrode array and improved methods of stimulating neural tissue. Whilethe invention has been described by means of specific embodiments andapplications thereof, it is understood that numerous modifications andvariations could be made thereto by those skilled in the art withoutdeparting from the spirit and scope of the invention. It is therefore tobe understood that within the scope of the claims, the invention may bepracticed otherwise than as specifically described herein.

What we claim is:
 1. A flexible circuit electrode array comprising: apolymer base layer; metal traces deposited on said polymer base layer,including electrodes suitable to stimulate neural tissue; said polymerbase layer and said metal traces are embedded in a body, said body beingcurved, and said polymer base layer is adapted to be electricallycoupled by a flexible circuit cable to an electronics package thatgenerates stimulation signals.
 2. The flexible circuit electrode arrayaccording to claim 1, wherein the body is curved to substantiallyconform to the curvature of a retina of a recipient's eye.
 3. Theflexible circuit electrode array according to claim 1, wherein the bodyis curved with a contracting radius at its edges.
 4. The flexiblecircuit electrode array according to claim 1, comprising 1 to 1000electrodes.
 5. The flexible circuit electrode array according to claim1, comprising 16 to 250 electrodes.
 6. The flexible circuit electrodearray according to claim 1, comprising 60 to 250 electrodes.
 7. Theflexible circuit electrode array according to claim 1 wherein theflexible circuit is from 0.3 mm to 0.7 mm wide.
 8. The flexible circuitelectrode array according to claim 1 wherein the flexible circuit isfrom 3.5 mm to 4.5 mm long.
 9. The flexible circuit electrode arrayaccording to claim 1 wherein the spacing between the electrodes is 5μm-500 μm.
 10. The flexible circuit electrode array according to claim 9wherein the spacing between the electrodes is 250 μm-500 μm.
 11. Theflexible circuit electrode array according to claim 10 wherein thespacing between the electrodes is 50 μm-500 μm.
 12. The flexible circuitelectrode array according to claim 1 wherein the electronic package has200 to 300 channels.
 13. The flexible circuit electrode array accordingto claim 1 wherein the electronic package has 240 to 260 channels. 14.The flexible circuit electrode array of claim 1, wherein the protectingmeans comprises polymer material embedding the flexible circuitelectrode array.
 15. The flexible circuit electrode array of claim 1,wherein the protecting means comprises pliable material along edges ofthe polymer base layer.
 16. The flexible circuit electrode array ofclaim 1, wherein the protecting means comprises an attachment point onthe polymer base layer, and wherein the attachment is adapted forholding a retinal tack and the retinal tack is adapted to hold theflexible circuit electrode array to the retina.
 17. An apparatus adaptedto apply at least one simulation signal to a recipient's eye,comprising: a flexible circuit cable adapted to pierce a sclera of therecipient's eye; an electronics package adapted to generate the at leastone stimulation signal to be applied to the recipient's eye and adaptedto be external to the sclera of the recipient's eye; a polymer baselayer adapted to be electrically coupled to the electronics package bythe flexible circuit cable; metal traces deposited on the polymer baselayer adapted to be electrically coupled to the electronics package bythe flexible circuit cable and including electrodes suitable tostimulate neural tissue; and means for protecting the retina of therecipient's eye, wherein the polymer base layer and the metal traces areembedded in a body, said body being curved such that it substantiallyconforms to the spherical curvature of the retina of the recipient'seye.
 18. The apparatus of claim 17, wherein the protecting meanscomprises pliable material along a length of the flexible circuit cable,and wherein the pliable material holds the flexible circuit electrodearray away from retinal tissue.
 19. The apparatus of claim 17, whereinthe protecting means comprises creating a service loop in the flexiblecircuit cable to allow lifting of the flexible circuit electrode arrayoff the retina without harming the retina.
 20. The apparatus of claim17, wherein the protecting means comprises creating a fold between thepolymer base layer and the flexible circuit cable to reduce tension andenable effective attachment of the flexible circuit electrode array tothe retina.